Small-fiber peripheral neuropathy is a common complication of chronic ethanol ingestion. In contrast to the acute analgesic action of ethanol in the central nervous system, pain is thought to result from effects of ethanol on the peripheral nervous system, inducing a small-fiber painful peripheral neuropathy. Although symptomatic therapy may provide some relief, in the majority of patients, treatment is at best only partially effective. Development of successful therapies has been hampered by lack of understanding of the cellular mechanisms within the primary afferent nerve fiber. Previous work in our laboratory established a model consisting of enhanced nociception in rats chronically consuming ethanol. We demonstrated mechanical and thermal hyperalgesia, hyperexcitability of sensory nerve fibers, and a critical contribution of the epsilon isoform of protein kinase C (PKCePSILON) to the enhanced nociception 46. Similar to what is observed clinically, ethanol withdrawal exacerbated the condition, and females were more susceptible to ethanol-induced hyperalgesia. Our investigation will focus on the pivotal role of PKCePsilon in ethanol-induced hyperalgesia. We hypothesize specific second messenger pathways most likely to stimulate PKCepsilon activity, and we outline a multidisciplinary approach to determine which of those pathways are responsible for ethanol-induced abnormalities in nociceptive nerve fiber activity as well as behavioral hyperalgesia. Furthermore, because recent observations have lead us to hypothesize that the pathways upstream to kinase activation in neuropathic nerve fibers may be strongly sex-dependent we will assess differences in mechanism between male and female animals. An ultimate goal of the present research proposal is to provide a rational basis for the design of novel strategies to treat pain in patients who chronically ingest ethanol, which may aid their attempts to moderate this behavior.